This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Unscheduled growth signals stimulated by a number of activated oncogenes induce the ARF tumor suppressor protein. ARF can activate a p53 response resulting in cell cycle arrest or apoptotic cell death. The ARF-p53 tumor suppressor pathway is one of the cell's major defense mechanisms against cancer induced by activating oncogenes and is dysfunctional in a large number of human tumor cells. The ARF signaling pathway to p53 remains to be elucidated The polyoma virus (Py) activating oncogene, middle T-antigen (PyMT), induces ARF but none of the Py proteins bind to and inactivate p53. We have shown that the polyoma virus small T-antigen (PyST) targets the ARF signaling pathway to p53 so that p53 is not upregulated when ARF is activated. This inhibition of p53 induction requires the Protein Phosphatase 2A (PP2A) binding domain of PyST revealing a previously unrecognized role of PP2A in the ARF-p53 signaling pathway. The PP2A binding domain is required for PyST to substitute for the PP2A B regulatory subunit and bind to the PP2A A scaffolding subunit and C catalytic subunit dimer to form a new PP2A complex. Thus PyST through its interaction with PP2A is highlighting a new aspect of the important ARF-p53 tumor-suppressor pathway. We plan to use proteomic, biological and biochemical approaches to determine how PyST influences PP2A and PP2A cellular targets to affect this important cellular pathway.